Assessing cancer risk after biologicals in rheumatological therapy

Recent data allow a more precise quantification of the malignancy risk of a Janus kinase inhibitor, which has been under discussion for some time.

Findings from new analysis of an open-label randomised controlled surveillance trial

What we knew so far

After an increased risk of certain neoplasms and infections emerged in pivotal trials of tofacitinib (first approved in 2012), the US Food and Drug Administration (FDA) ordered post-marketing studies. These began in 2014 and initial results were published about a year ago in the New England Journal of Medicine, which reinforced the warnings.2 More recently, a more comprehensive report on this surveillance data was published, providing additional details on malignancy risk, including rates of specific tumours, and comparing these with the risk with TNF inhibitors.3

A more precise picture of risks through a long-term safety study

The 'ORAL' surveillance study reports an increased risk of malignancy with tofacitinib compared to tumour necrosis factor (TNF) inhibitors. 4,362 patients over 50 years of age (from 30 countries) with rheumatoid arthritis, and at least one other cardiovascular risk factor, were randomised 1:1:1 to 10 or 5 mg of tofacitinib twice daily, or one of two TNF inhibitors. For example, adalimumab was used in North America, etanercept elsewhere, both at standard doses. All patients continued to take methotrexate. After an interim analysis in 2019 showed an increased mortality rate under the higher tofacitinib dose, patients in this group were switched to the lower dose.

Previous studies have already described an increased risk for cardiovascular and malignant diseases in people with RA compared to the general population. In the current evaluation, the risk for malignancies diverged again after month 18. Tofacitinib at doses of 5 or 10 mg, taken twice daily, was associated with a rate of 1.13 cancers per 100 patient-years (versus 0.77 among TNF inhibitors). This corresponds to a hazard ratio of 1.48 (95% CI 1.04-2.09) for tofacitinib compared to TNFi.2,3

Lymphoma had been among the first cancers to be the subject of attention, and the new data showed a hazard ratio of 5.09 for the two tofacitinib doses combined compared to TNF inhibitors (although the figure is subject to large statistical uncertainty as there were only 10 lymphoma cases in total). Lung cancer was the most frequently documented tumour type in tofacitinib-treated patients. This appeared to occur significantly more often under tofacitinib (HR 2.17), as did squamous cell carcinomas of the skin (HR 2.32) and non-melanocytic skin cancers (NMSC, HR 2.02).

Conclusion and issues for medical practice

Cancer incidence was highest in patients with a history of cardiovascular disease or elevated cardiovascular risk scores in all treatment arms, which may be due to shared risk factors for cardiovascular pathology and cancer. For 5 years of tofacitinib treatment, the Number Needed to Harm (NNH) was 55 - so if you treat 55 patients for 5 years, compared to what would be expected with TNF inhibitors, one additional cancer case occurs with tofacitinib.2,3

Many doctors are reluctant to use steroids due to undesirable side effects, but, the "heavy guns", biologics, also present us with a dilemma as they have serious and potentially lethal side effects, e.g. fungal or amoebic infections or PML (Progressive multifocal leukoencephalopathy). "The problem is also that these adverse events occur several years after the use of the biologics. Numerous people suffered life-threatening sepsis after using rituximab years earlier," an epidemiologist commented on the issue.2 Do people want to run the risk of increased cancer risk for treatment of psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis or ulcerative colitis? And how do doctors communicate this when starting therapy?

  1. In German only: Gelbe Liste. Tofacitinib - Anwendung, Wirkung, Nebenwirkungen | Gelbe Liste. Gelbe Liste Online
  2. Xeljanz Cancer Risks Detailed. (2022).
  3. Curtis, J. R. et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Annals of the Rheumatic Diseases (2022) doi:10.1136/ard-2022-222543.

    Last site visits: 29.01.23